PROJECT SUMMARY . In psychiatry, we are limited by the mismatch between the diverse heterogeneity of the brain and the tools we have to treat it. We know from anatomic, cortical mapping, and imaging studies that every several millimeters of the brain is constituted, connected, and functions in a unique and significantly different manner. However, the current standard of care for many if not most psychiatric diseases is delivery of a small molecule drug to the entire body, with the hope that this nonspecific delivery will somehow have the right specific effect on the right part of the brain, without significant nonspecific action in the rest of the brain or body. What if instead we could deliver the right drug, to the right part of the brain, at the right time? We can do exactly that by combining ?phase-change? nanoparticle-based drug delivery and MRI-guided focused ultrasound. In doing so, we could obtain spatiotemporally precise and noninvasive control of neuromodulatory inputs, with an immediate path for clinical translation. In eventual clinical usage, phase-change nanoparticles that are loaded with the desired drug will be infused intravenously into a patient. The nanoparticles will redistribute throughout the blood pool in their inert form. Then, focused ultrasound will be applied only to the part of the brain where drug activity is desired. Ultrasound will induce drug release from the nanoparticles into the intravascular space. The drug will then rapidly cross the blood-brain barrier to act only in the sonicated region of the brain. Throughout this procedure, the patient will be otherwise awake and able to participate in a neuropsychiatric assessment, functional brain imaging, and/or cognitive behavioral therapy. The uncaging sonication could be repeated or applied to one or more additional brain regions throughout the time that the nanoparticles reside in the blood pool. Importantly, this technology could serve as a platform for brain-mapping studies that need to specifically modulate only one biochemical pathway in one brain region of one neural circuit. This would also have significant advantages for clinical care by maximizing therapeutic effect while limiting side effects, and for allowing pseudo-lesion studies to map functional brain regions prior to neurosurgery. In this proposal, we will build upon our preliminary data to refine the specificity and potency of this technique, and lay the groundwork for clinical translation: (1) we will establish a protocol for production of these nanoparticles that is scalable for larger animals and for humans, and that is compatible with established standards for clinical administration; (2) using combined focused ultrasound and EEG in rats, we will determine the temporal resolution and kinetics of the neuromodulatory effect induced by localized release of the small molecule anesthetic propofol by ultrasonic uncaging from our nanoparticles; and (3) using combined focused ultrasound and PET imaging in rats, we will quantify the spatial extent and resolution of localized propofol release from our nanoparticles by visualizing its effect on GABAA receptor binding. Following successful completion of these foundational experiments, we will build on this proposal by moving rapidly towards clinical translation.